The present invention relates to a class of sulphonyl derivatives which act on serotonin receptors (also known as 5-hydroxytryptamine or 5-HT receptors). More particularly, the invention concerns phenylsulphonyl derivatives wherein the sulphonyl moiety is also attached to an N-arylalkyl-substituted azetidine, pyrrolidine or piperidine ring. These compounds are selective antagonists of the human 5-HT2A receptor and are therefore useful as pharmaceutical agents, especially in the treatment and/or prevention of adverse conditions of the central nervous system, including psychotic disorders such as schizophrenia.
Schizophrenia is a disorder which is conventionally treated with drugs known as neuroleptics. In many cases, the symptoms of schizophrenia can be treated successfully with so-called xe2x80x9cclassicalxe2x80x9d neuroleptic agents such as haloperidol. Classical neuroleptics generally are antagonists at dopamine D2 receptors.
Notwithstanding their beneficial antipsychotic effects, classical neuroleptic agents such as haloperidol are frequently responsible for eliciting acute extrapyramidal symptoms (movement disorders) and neuroendocrine (hormonal) disturbances. These side-effects, which plainly detract from the clinical desirability of classical neuroleptics, are believed to be attributable to D2 receptor blockade in the striatal region of the brain.
The compound (+)-xcex1-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol (also known as MDL-100,907) is described in WO 91/18602. In preclinical studies, MDL-100,907 failed to induce catalepsy and failed to block apomorphine-induced stereotyped behaviour in animal models, strongly suggesting that this compound would be free from any liability to cause extrapyramidal side-effects. MDL-100,907 is currently undergoing clinical trials in schizophrenic patients and has demonstrated efficacy in a multicentre, placebo-controlled study for antipsychotic potential, with no neurological adverse effects. Pharmacologically, MDL-100,907 has been shown to be a potent antagonist of human 5-HT2A receptors, whilst being essentially devoid of activity at the human dopamine D2 receptor. It is accordingly believed that compounds which can interact selectively with the 5-HT2A receptor relative to the dopamine D2 receptor will display the beneficial level of antipsychotic activity associated with 5-HT2A receptor antagonism, whilst minimizing or even avoiding the extrapyramidal and other side-effects arising from an interaction with dopamine D2 receptors.
The compounds of the present invention are potent antagonists of the human 5-HT2A receptor, and are accordingly of benefit in the treatment and/or prevention of psychotic disorders such as schizophrenia. The compounds of the invention may display more effective binding to the human 5-HT2A receptor than to the human dopamine D2 receptor, and they can therefore be expected to manifest fewer side-effects than compounds which do not discriminate in their binding affinity as between 5-HT2A and D2 receptors.
By virtue of their potent human 5-HT2A receptor antagonist activity; the compounds of the present invention are also effective in the treatment, of neurological conditions including depression, anxiety, panic disorder, obsessive-compulsive disorder, pain, sleep disorders such as insomnia, eating disorders such as anorexia nervosa, and dependency or acute toxicity associated with narcotic agents such as LSD or MDMA; and moreover are beneficial in controlling the extrapyramidal symptoms associated with the administration of neuroleptic agents. They may further be effective in the lowering of intraocular pressure and may therefore be beneficial in treating glaucoma (cf. T. Mano et al. and H. Takaneka et al., Investigative Ophthalmitology and Visual Scienice, 1995, vol. 36, pages 719 and 734 respectively).
Being 5-HT2A receptor antagonists, the compounds of the present invention may also be beneficial in preventing or reducing the toxic symptoms associated with the intake of ergovaline in animals consuming Acremonium coenophialum infected tall fescue (cf. D. C. Dyer, Life Sciences, 1993, 53, 223-228).
Various classes of compounds containing inter alia a sulphonyl moiety, which are stated to have activity as antipsychotic agents, are described in WO 96/35666, EP-A-0261688, and U.S. Pat. Nos. 4,218,455 and 4,128,552. A further series of compounds, containing inter alia a piperidinyl-sulphonyl-indole moiety, is described in U.S. Pat. No. 5,418,242, and alleged to possess analgesic properties. DE-A-3901735 relates to the use of a class of compounds containing inter alia a sulphonylpyridine moiety in the treatment of depression. None of these publications, however, discloses or suggests the particular class of phenylsulphonyl derivatives provided by the present invention.
The compounds according to the present invention are potent and selective 5-HT2A receptor antagonists having a human 5-HT2A receptor binding affinity (Ki) of 100 nM or less, typically of 50 nM or less and preferably of 10 nM or less. The compounds of the invention may possess at least a 10-fold selective affinity, suitably at least a 20-fold selective affinity and preferably at least a 50-fold selective affinity, for the human 5-HT2A receptor relative to the human dopamine D2 receptor.
The present invention provides a compound of formula I, or a salt thereof: 
wherein
Z represents hydrogen, halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy, xe2x80x94ORa, xe2x80x94SRa, xe2x80x94SORa, xe2x80x94SO2Ra, xe2x80x94SO2NRaRb, xe2x80x94NRaRb, xe2x80x94NRaCORb, xe2x80x94NRaCO2Rb, xe2x80x94CORa, xe2x80x94CO2Ra or xe2x80x94CONRaRb; or
Z represents an optionally substituted five-membered heteroaromatic ring selected from furan, thiophene, pyrrole, oxazole, thiazole, isoxazole, isothiazole, imidazole, pyrazole, oxadiazole, thiadiazole, triazole and tetrazole; or
Z represents an optionally substituted six-membered heteroaromatic ring selected from pyridine, pyrazine, pyrimidine and pyridazine;
Ra and Rb independently represent hydrogen or C1-6 alkyl; or Ra and Rb, when linked through a nitrogen atom, together represent the residue of an azetidine, pyrrolidine, piperidine or morpholine ring;
E represents a chemical bond or a straight or branched alkylene chain containing from 1 to 4 carbon atoms, optionally incorporating an oxygen atom to form an ether linkage;
M represents the residue of an azetidine, pyrrolidine or piperidine ring;
R1 represents an optionally substituted aryl(C2-4)alkyl group; and
R2 represents hydrogen or halogen.
Where Z in the compounds of formula I above represents a five-membered heteroaromatic ring, this ring may be optionally substituted by one or, where possible, two substituents. As will be appreciated, where Z; represents an oxadiazole, thiadiazole or tetrazole ring, only one substituent will be possible; otherwise, one or two optional substituents may be accommodated around the five-membered heteroaromatic ring Z.
Where Z in the compounds of formula I above represents a six-membered heteroaromatic ring, this ring may be optionally substituted by one or more substituents, typically by one or two substituents.
Examples of suitable substituents on the five-membered or six-membered heteroaromatic ring as specified for Z include halogen, cyano, trifluoromethyl, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, amino, C1-6 alkylamino and di(C1-6)alkylamino, especially methyl.
The aryl(C2-4)alkyl group R1 may be optionally substituted by one or more substituents. Suitably, the aryl(C2-4)alkyl group R1 is unsubstituted, or substituted by one, two or three substituents. More particularly, the aryl(C2-4)alkyl group R1 may be unsubstituted, or substituted by one or two substituents. Any optional substitution on the aryl(C2-4)alkyl group R1 will suitably be on the aryl moiety thereof, although substitution on the alkyl moiety thereof is an alternative possibility.
Representative examples of optional substituents on the group R1 include halogen, nitro, trifluoromethyl, trifluoromethoxy, C1-6 alkyl, keto, hydroxy, C1-6 alkoxy, C1-6 alkylthio or di(C1-6)alkylamino.
Illustrative examples of optional substituents on the group R1 include halogen, nitro, trifluoromethyl, trifluoromethoxy, C1-6 alkyl, hydroxy, C1-6 alkoxy, C1-6 alkylthio or di(C1-6)alkylamino.
As used herein, the expression xe2x80x9cC1-6 alkylxe2x80x9d includes methyl and ethyl groups, and straight-chained or branched propyl, butyl, pentyl and hexyl groups. Particular alkyl groups are methyl, ethyl, n-propyl, isopropyl and tert-butyl. Derived expressions such as xe2x80x9cC1-6 alkoxyxe2x80x9d, xe2x80x9cC1-6 alkylthioxe2x80x9d and xe2x80x9cC1-6 alkylaminoxe2x80x9d are to be construed accordingly.
Typical aryl groups include phenyl and naphthyl, preferably phenyl.
The expression xe2x80x9caryl(C2-4)alkylxe2x80x9d as used herein includes phenylethyl, phenylpropyl and naphthylethyl, especially phenylethyl.
The term xe2x80x9chalogenxe2x80x9d as used herein includes fluorine, chlorine, bromine and iodine, especially fluorine or chlorine.
For use in medicine, the salts of the compounds of formula I will be pharmaceutically acceptable salts. Other salts may, however, be useful in the preparation of the compounds according to the invention or of their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds of this invention include acid addition salts which may, for example, be formed by mixing a solution of the compound according to the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulphuric acid, methanesulphonic acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g. sodium or potassium salts; alkaline earth metal salts, e.g. calcium or magnesium salts; and salts formed with suitable organic ligands, e.g. quaternary ammonium salts.
Where the compounds according to the invention have at least one asymmetric centre, they may accordingly exist as enantiomers. Where the compounds according to the invention possess two or more asymmetric centres, they may additionally exist as diastereoisomers. It is to be, understood that all such isomers and mixtures thereof in any proportion are encompassed within the scope of the present invention.
Typically, the substituent Z in the compounds of formula I above represents hydrogen, halogen, cyano, xe2x80x94NRaCORb, xe2x80x94CO2Ra or xe2x80x94CONRaRb; or an optionally substituted five-membered ring as specified above.
Suitably, the substituent Z represents hydrogen, cyano, xe2x80x94NRaCORb or xe2x80x94CONRaRb; or an optionally substituted five-membered ring as specified above.
Suitably, Ra represents hydrogen or methyl, especially hydrogen.
Suitably, Rb represents hydrogen or methyl, especially hydrogen.
Where the group Z represents an optionally substituted five-membered heteroaromatic ring, this is suitably an imidazole, pyrazole, 1,2,3-triazole, 1,2,4-triazole or tetrazole ring, any of which may be optionally substituted, typically by methyl.
Specific values for the group Z include hydrogen, bromo, cyano, acetylamino, methoxycarbonyl, carboxamido, imidazol-1-yl, pyrazol-1-yl, 1,2,3-triazol-1-yl, 1,2,4-triazol-1-yl, 1-methyl-1,2,4-triazol-5-yl, tetrazol-1-yl and 2-methyltetrazol-5-yl.
Particular values for the group Z include hydrogen, cyano, acetylamino, carboxamido, imidazol-1-yl, pyrazol-1-yl, 1,2,3-triazol-1-yl, 1,2,4-triazol-1-yl, 1-methyl-1,2,4-triazol-5-yl, tetrazol-1-yl and 2-methyltetrazol-5-yl.
One specific value of Z is carboxamido.
Another specific value of Z is cyano.
Where E represents a straight or branched alkylene chain, this may be, for example, methylene, ethylene, 1-methylethylene, propylene, 2-methylpropylene or butylene. The alkylene chain E may optionally incoporate an oxygen atom, thereby forming an ether linkage. Moreover, E may represent a chemical bond such that the moiety Z is attached directly to the phenyl ring as depicted in formula I above.
Preferably, E represents a chemical bond or a methylene linkage.
In a specific embodiment, E represents a chemical bond.
In one particular configuration, the moiety Zxe2x80x94Exe2x80x94 in the compounds of formula I is attached at the para position relative to the sulphonyl group, in which case the present invention suitably provides a compound of formula IA, or a salt thereof: 
wherein Z, E, M, R1 and R2 are as defined above.
The moiety M preferably represents the residue of a piperidine ring, in which case the present invention suitably provides a compound of formula IB, or a salt thereof: 
wherein Z, E, R1 and R2 are as defined above.
Suitably, R1 represents optionally substituted phenylethyl or optionally substituted phenylpropyl. In addition, R1 may represent optionally substituted naphthylethyl.
Preferably, R1 represents phenylethyl, which may be unsubstituted, or substituted by one or more substituents. Typically, the phenylethyl group R1 will be unsubstituted, or substituted by one, two or three (especially one or two) substituents. In a particular embodiment, R1 represents disubstituted phenylethyl.
Examples of specific substituents on the group R1 include fluoro, chloro, bromo, iodo, nitro, trifluoromethyl, methyl, keto, hydroxy, methoxy, methylthio and dimethylamino.
Particular examples of optional substituents on R1 include fluoro, chloro, bromo, iodo, nitro, trifluoromethyl, methyl, hydroxy, methoxy, methylthio and dimethylamino.
Specific examples of optional substituents on R1 include fluoro, chloro and keto, especially fluoro.
Representative values of R1 include phenylethyl, fluoro-phenylethyl, chloro-phenylethyl, bromo-phenylethyl, iodo-phenylethyl, difluoro-phenylethyl, dichloro-phenylethyl, (chloro)(fluoro)-phenylethyl, (fluoro)-(trifluoromethyl)-phenylethyl, (bromo)(methoxy)-phenylethyl, trifluoro-phenylethyl, nitro-phenylethyl, methyl-phenylethyl, hydroxy-phenylethyl, methoxy-phenylethyl, dimethoxy-phenylethyl, (hydroxy)(methoxy)-phenylethyl, (hydroxy)(dimethoxy)-phenylethyl, trimethoxy-phenylethyl, methylthio-phenylethyl, dimethylamino-phenylethyl, phenylpropyl, hydroxy-phenylpropyl and naphthylethyl. Additional values of R1 include fluorophenyl-oxoethyl and chlorophenyl-oxoethyl.
Typical values of R1 include phenylethyl, fluoro-phenylethyl, chloro-phenylethyl, difluoro-phenylethyl, fluorophenyl-oxoethyl and chlorophenyl-oxoethyl.
Particular values of R1 include phenylethyl, fluoro-phenylethyl, chloro-phenylethyl and difluoro-phenylethyl.
Suitably, R1 may represent 2-phenylethyl, 2-fluoro-2-phenylethyl, 2-(4-fluorophenyl)ethyl, 2-(2-chlorophenyl)ethyl, 2-(2,4-difluorophenyl)ethyl, 2-(4-fluorophenyl)-2-oxoethyl or 2-(4-chlorophenyl)-2-oxoethyl.
One specific value of R1 is 2-(2,4-difluorophenyl)ethyl.
Another specific value of R1 is 2-(4-fluorophenyl)-2-oxoethyl.
Suitably, R2 represents hydrogen or fluoro, especially hydrogen.
A particular sub-class of compounds according to the invention is represented by the compounds of formula IIA, and salts thereof: 
wherein
Z and E are as defined with reference to formula I above;
R11 and R12 independently represent hydrogen, halogen, nitro, trifluoromethyl, C1-6 alkyl, hydroxy, C1-6 alkoxy, C1-6 alkylthio or di(C1-6)alkylamino;
R13 represents hydrogen and R14 represents hydrogen or fluoro, or R13 and R14 together represent keto; and
R21 represents hydrogen or fluoro.
Suitably, R11 represents hydrogen, fluoro, chloro or methoxy, especially hydrogen or fluoro.
Suitably, R12 represents hydrogen, fluoro, chloro, bromo, iodo, nitro, trifluoromethyl, methyl, hydroxy, methoxy, methylthio or dimethylamino. More particularly, R12 may represent hydrogen, fluoro or chloro.
In one embodiment of the compounds of formula IIA above, R13 represents hydrogen and R14 represents hydrogen or fluoro.
In another embodiment of the compounds of formula IIA, R13 and R14 together represent keto.
Suitably, R13 and R14 are both hydrogen.
Suitably, R21 is hydrogen.
Another sub-class of compounds according to the invention is represented by the compounds of formula IIB, and salts thereof: 
wherein
Z, E and R1 are as defined with reference to formula I above; and
R21 is as defined with reference to formula IIA above.
A particular subset of the compounds of formula IIA and IIB above is represented by the compounds of formula IIC, and salts thereof: 
wherein Z, E, R11, R12, R13, R14 and R21 are as defined above.
In one embodiment of the compounds of formula IIC above, R13 and R14 are both hydrogen.
Specific compounds within the scope of the present invention include:
4-(4-cyanophenylsulphonyl)-1-[2-(2,4-difluorophenyl)ethyl]piperidine;
4-(4-acetylaminophenylsulphonyl)-1-[2-(2,4-difluorophenyl)ethyl]-piperidine;
4-(4-cyano-3-fluorophenylsulphonyl)-1-[2-(2,4-difluorophenyl)ethyl]-piperidine;
1-[2-(2,4-difluorophenyl)ethyl]-4-[4-(1,2,4-triazol-1-yl)phenylsulphonyl]-piperidine;
1-[2-(2,4-difluorophenyl)ethyl]-4-[4-(imidazol-1-yl)phenylsulphonyl]-piperidine;
1-[2-(2,4-difluorophenyl)ethyl]-4-[4-(pyrazol-1-yl)phenylsulphonyl]-piperidine;
1-[2-(2,4-difluorophenyl)ethyl]-4-[4-(1,2,3-triazol-1-yl)phenylsulphonyl]-piperidine;
4-(4-carboxamidophenylsulphonyl)-1-[2-(2,4-difluorophenyl)ethyl]-piperidine;
4-(4-carboxamido-3-fluorophenylsulphonyl)-1-[2-(2,4-difluorophenyl)ethyl]-piperidine;
1-[2-(2,4-difluorophenyl)ethyl]-4-[4-(2-methyltetrazol-5-yl)-phenylsulphonyl]piperidine;
1-[2-(2,4-difluorophenyl)ethyl]-4-[4-(1-methyl-1,2,4-triazol-5-yl)-phenylsulphonyl]piperidine;
1-[2-(2,4-difluorophenyl)ethyl]-4-[4-(tetrazol-1-ylmethyl)phenylsulphonyl]-piperidine;
4-(4-carboxamidophenylsulphonyl)-1-(2-phenylethyl)piperidine;
4-(4-carboxamidophenylsulphonyl)-1-[2-(4-fluorophenyl)ethyl]piperidine;
4-(4-carboxamidophenylsulphonyl)-1-[2-(2-chlorophenyl)ethyl]piperidine;
4-(4-carboxamidophenylsulphonyl)-1-(2-fluoro-2-phenylethyl)piperidine;
1-[2-(2,4-difluorophenyl)ethyl]-4-phenylsulphonylpiperidine;
4-(3-carboxamidophenylsulphonyl)-1-[2-(2,4-difluorophenyl)ethyl]-piperidine;
4-(4-bromophenylsulphonyl)-1-[2-(4-fluorophenyl)-2-oxoethyl]piperidine;
4-(4-cyanophenylsulphonyl)-1-[2-(4-fluorophenyl)-2-oxoethyl]piperidine;
1-[2-(4-fluorophenyl)-2-oxoethyl]-4-phenylsulphonylpiperidine;
1-[2-(4-chlorophenyl)-2-oxoethyl]-4-phenylsulphonylpiperldine;
and salts thereof.
The invention also provides pharmaceutical compositions comprising one or more of the compounds according to this invention in association with a pharmaceutically acceptable carrier. Preferably these compositions are in unit dosage forms such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, auto-injector devices or suppositories; for oral, parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation. Alternatively, the compositions may be presented in a form suitable for once-weekly or once-monthly administration; for example, an insoluble salt of the active compound, such as the decanoate salt, may be adapted to provide a depot preparation for intramuscular injection. An erodible polymer containing the active ingredient may be envisaged. For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, or a pharmaceutically acceptable salt thereof. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention. Favoured unit dosage forms contain from 1 to 100 mg, for example 1, 2, 5, 10, 25, 50 or 100 mg, of the active ingredient. The tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric. acids with such materials as shellac, cetyl alcohol and cellulose acetate.
The liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include aqueous solutions, suitably flavoured syrups, aqueous or oil suspensions, and flavoured emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin.
In the treatment of schizophrenia, a suitable dosage level is about 0.01 to 250 mg/kg per day, preferably about 0.05 to 100 mg/kg per day, and especially about 0.05 to 5 mg/kg per day. The compounds may be administered on a regimen of 1 to 4 times per day.
If desired, the compounds according to this invention may be co-administered with another anti-schizophrenic medicament, for example one producing its effects via dopamine D2 and/or D4 receptor subtype blockade. In such circumstances, an enhanced anti-schizophrenic effect may be envisaged without a corresponding increase in side-effects such as those caused by, for example, D2 receptor subtype blockade; or a comparable anti-schizophrenic effect with reduced side-effects may alternatively be envisaged. Such co-administration may be desirable where a patient is already established on an anti-schizophrenic treatment regime involving conventional anti-schizophrenic medicaments. Suitable anti-schizophrenic medicaments of use in combination with the compounds according to the present invention include haloperidol, chlorpromazine, mesoridazine, thioridazine, acetophenazine, fluphenazine, perphenazine, trifluoperazine, chloroprothixene, thiothixene, clozapine, olanzapine, pimozide, molindone, loxapine, sulpiride, risperidone, xanomeline, fananserin and ziprasidone, and pharmaceutically acceptable salts thereof.
The compounds according to the present invention may be prepared by a process which comprises attachment of the R1 moiety to a compound of formula III: 
wherein Z, E, M and R2 are as defined above; by conventional means including N-alkylation.
Attachment of the R1 moiety to the compounds of formula III may conveniently be effected by standard alkylation techniques. One example thereof comprises treatment with an aryl(C2-4)alkyl halide, especially a bromide derivative R1xe2x80x94Br such as 2-phenylethyl bromide or 2-(2,4-difluorophenyl)ethyl bromide, typically under basic conditions, e.g. potassium carbonate or caesium carbonate, in a solvent such as acetonitrile or N,N-dimethylformamide, suitably at an elevated temperature and optionally in the presence of sodium iodide. Another example comprises treatment of the compound of formula III with an aryl(C2-4)alkyl mesylate R1xe2x80x94OSO2CH3 such as 2-phenylethyl methanesulphonate, typically in the presence of sodium carbonate and sodium iodide, in a suitable solvent such as 1,2-dimethoxyethane.
Alternatively, the R1 moiety may conveniently be attached by reductive alkylation, which may be accomplished in a single step, or as a two-step procedure. The single-step approach, for the preparation of a compound of formula I wherein R1 corresponds to a group of formula xe2x80x94CH2Rla, suitably comprises treating the required compound of formula III as defined above with the appropriate aldehyde of formula Rlaxe2x80x94CHO, e.g. phenylacetaldehyde, in the presence of a reducing agent such as sodium cyanoborohydride. In a typical two-step procedure, a carboxylic acid derivative of formula Rlaxe2x80x94CO2H is condensed with the required compound of formula III, suitably in the presence of a condensing agent such as (i) bis(2-oxo-3-oxazolidinyl)phosphinic chloride and triethylamine, or (ii) 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 1-hydroxybenzotriazole hydrate, to afford a compound corresponding to formula I wherein R1 represents xe2x80x94CORla; the carbonyl group thereof can then be reduced, for example by treatment with borane-tetrahydrofuran complex, or with dilsobutylaluminium hydride, and the required compound of formula I thereby obtained.
The compounds of formula III above may be prepared by oxidation of the corresponding compound of formula IV: 
wherein Z, E, M and R2 are as defined above, and Rp represents an amino-protecting group; with subsequent removal of the amino-protecting group Rp.
The amino-protecting group Rp in the compounds of formula IV is suitably a carbamoyl moiety such as tert-butoxycarbonyl (BOC), which can readily be removed as required by treatment under acidic conditions, e.g. in refluxing methanolic hydrochloric acid.
Similarly, the compounds according to the invention may be prepared by a process which comprises oxidizing a compound of formula V: 
wherein Z, E, M, R1 and R2 are as defined above.
Oxidation of the compounds of formula IV or V may conveniently be accomplished by treating the appropriate substrate with an oxidizing agent. Typical oxidizing agents of use in this transformation include meta-chloroperbenzoic acid and Oxone(copyright). In an alternative procedure, compound IV or V may be oxidized by treatment with ruthenium(IV) oxide and sodium periodate in a suitable solvent which may typically comprise a mixture of carbon tetrachloride and aqueous acetonitrile.
The intermediates of formula IV and V may be prepared by reacting a compound of formula VI with a compound of formula VII: 
wherein Z, E, M and R2 are as defined above, Rlb represents an amino-protecting group Rp or corresponds to the moiety R1 as defined above, and L1 represents a suitable leaving group.
The leaving group L1 in the compounds of formula VII above suitably represents a C1-4 alkylsulphonyloxy group such as methanesulphonate (mesylate), in which case the desired intermediate of formula VII can be prepared from the corresponding precursor compound of formula VII wherein LI represents hydroxy by mesylation under standard conditions.
The reaction between compounds VI and VII is conveniently effected in a solvent such as acetonitrile, generally in the presence of a base such as potassium carbonate, suitably at an elevated temperature which might typically be the reflux temperature of the solvent employed.
Where they are not commercially available, the starting materials of formula VI may be prepared by procedures analogous to those described in the accompanying Examples, or by standard methods well known from the art.
It will be appreciated that any compound of formula I initially obtained from any of the above processes may, where appropriate, subsequently be elaborated into a further desired compound of formula I using techniques known from the art. For example, a compound of formula I initially obtained wherein the moiety Zxe2x80x94Exe2x80x94 represents bromo may be converted into the corresponding compound of formula I wherein the moiety Zxe2x80x94Exe2x80x94 represents cyano by treatment with copper(I) cyanide in the presence of 1-methyl-2-pyrrolidinone (NMP), or with zinc cyanide in the presence of tetrakis(triphenylphosphine)palladium(O). The resulting compound of formula I wherein the moiety Zxe2x80x94Exe2x80x94 represents cyano thereby obtained may in turn be converted into the corresponding compound of formula I wherein the moiety Zxe2x80x94Exe2x80x94 represents carboxamido by heating in mineral acid, e.g. 85% sulphuric acid at 100xc2x0 C., or by treatment with potassium trimethylsilanolate, typically in tetrahydrofuran at reflux. Alternatively, a compound of formula I initially obtained wherein the moiety Zxe2x80x94Exe2x80x94 represents bromo may be converted directly into the corresponding compound of formula I wherein the moiety Zxe2x80x94Exe2x80x94 represents carboxamido by heating under a carbon monoxide atmosphere in the presence of 1,1,1,3,3,3-hexamethyldisilazane, dilsopropylamine, palladium(II) acetate and 1,3-bis(diphenylphosphino)propane. Where, for example, the moiety Zxe2x80x94Exe2x80x94 in the compounds of formula I represents an optionally substituted N-linked pyrrole, imidazole, pyrazole, triazole or tetrazole moiety, e.g. imidazol-1-yl, pyrazol-1-yl, 1,2,3-triazol-1-yl or 1,2,4-triazol-1-yl, these compounds may be prepared by treating the corresponding compound of formula I wherein Zxe2x80x94Exe2x80x94 represents bromo with the appropriate optionally substituted pyrrole, imidazole, pyrazole, triazole or tetrazole derivative, in the presence of copper bronze and sodium hydride, typically with heating in NMP. Where, for example, the moiety Zxe2x80x94Exe2x80x94 in the compounds of formula I represents an optionally substituted C-linked five-membered heteroaromatic ring, e.g. 2-methyltetrazol-5-yl or 1-methyl-1,2,4-triazol-5-yl, these compounds may be prepared by reacting the corresponding compound of formula I wherein Zxe2x80x94Exe2x80x94 represents bromo with a tributylstannyl derivative of the appropriate heteroaromatic compound, e.g. 2-methyl-5-tributylstannyltetrazole or 1-methyl-5-tributylstannyl-1,2,4-triazole, in the presence of a transition metal catalyst such as tetrakis(triphenylphosphine)palladium(O), typically with heating in a solvent such as N,N-dimethylformamide. A compound of formula I wherein, for example, Z represents a tetrazol-1-yl moiety and E is methylene may be prepared from the corresponding compound of formula I wherein the moiety Zxe2x80x94Exe2x80x94 represents hydroxymethyl, by mesylation under standard conditions followed by displacement of the mesyl group by treatment with tetrazole, typically in the presence of sodium iodide and a base such as caesium carbonate; the compound of formula I wherein Zxe2x80x94Exe2x80x94 represents hydroxymethyl may suitably be prepared by diisobutylaluminium hydride (DIBAL-H) reduction of the corresponding compound of formula I wherein Zxe2x80x94Exe2x80x94 represents a C2-6 alkoxycarbonyl group, e.g. methoxycarbonyl, which in turn may be prepared by treatment of the corresponding compound of formula I wherein Zxe2x80x94Exe2x80x94 represents bromo with 1,1xe2x80x2-bis(diphenylphosphino)ferrocene; palladium(II) acetate, triethylamine and a C1-6 alkanol such as methanol, in an atmosphere of carbon monoxide. A compound of formula I wherein Zxe2x80x94Exe2x80x94 represents C2-6 alkoxycarbonyl, e.g. methoxycarbonyl, may be converted to the corresponding compound of formula I wherein Zxe2x80x94Exe2x80x94 represents carboxamido by treatment with ammonium chloride in the presence of trimethylaluminium.
Where the above-described processes for the preparation of the compounds of use in the invention give rise to mixtures of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. The compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution. The compounds may, for example, be resolved into their component enantiomers by standard techniques such as preparative HPLC, or the formation of diastereomeric pairs by salt formation with an optically active acid, such as (xe2x88x92)-di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toluoyl-l-tartaric acid, followed by fractional crystallization and regeneration of the free base. The compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary.
During any of the above synthetic sequences it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley and Sons, 1991. The protecting groups may be removed at a convenient subsequent, stage using methods known from the art.